tbuckley/cabot-search huggingface dataset:
Abstract 15208: Association Between Electrocardiographic St-t Wave Abnormalities and Stroke Risk in the Allhat Trial
Authors: Binaya Basyal, Amit K Dey, Aparna Sajja, Aditya A Joshi, Kumar Ashish, Allen J Taylor
Journal: Circulation (2022)

Background: The presence of electrocardiographic (ECG) ST-T wave abnormalities has previously been shown to be associated with increased risk of coronary artery disease but their association with stroke incidence is unclear.Objective: We sought to investigate the relationship between ST-T wave abnormalities and stroke incidence in the ALLHAT trial. Methods: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized double-blinded clinical trial (n=33,357) conducted from 1994 through 2002, examining whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers incidence of CHD or CVD events compared to treatment with a diuretic. Major ST depression or T wave inversion on any ECG in the past 2 years were included in the study. One of the secondary outcomes included in the study was incident stroke. Hazard ratios (relative risks [RRs]) and 95% confidence intervals (CIs) were obtained using Cox proportional hazards regression model. All statistical analyses were performed using STATA 12 (Stata Corp., College Station, TX, USA). Results: Study participants were predominantly middle-aged, male, white, with prevalence of ST-T wave abnormality being 10.35% (N=3,420). Presence of ST-T wave abnormalities were not associated with a higher risk of stroke [hazard ratio 0.47 (95% CI, 0.91-1.22)] in unadjusted analyses. This relationship was not significant even after adjustment for prevalent cardiovascular disease (CABG, ASCVD) [0.51(95% CI, 0.91- 1.22)], cardiovascular risk factors (age, sex, diabetes, systolic blood pressure, diastolic blood pressure, cholesterol, BMI) [0.15 (95% CI, 0.96-1.31)] as well as randomized treatment groups in ALLHAT [0.15 (95% CI, 0.96-1.31)]. Conclusion: Presence of major ST-T wave abnormality does not predict incident stroke in the the ALLHAT trial, more observations from contemporary studies need to be elucidated.
Abstract 15126: Hybrid Supervised and Unsupervised Machine Learning Model Improves Prediction of New-Onset Dialysis in Orthotopic Heart Transplant Patients
Authors: Roshan Mathi, Weston McDonald, Benjamin Usry, Khaled Shorbaji, Brett Welch, Arman Kilic
Journal: Circulation (2022)

Introduction: Machine learning (ML) approaches to clinical risk prediction have demonstrated improved performance over traditional statistical approaches. New-onset dialysis following isolated orthotopic heart transplantation (OHT) is an important contributor to mortality risk and quality of life in recipients, yet traditional approaches to predicting its occurrence have performed only modestly. This study sought to develop and evaluate a hybrid supervised and unsupervised ML approach to estimating the risk of new-onset dialysis following OHT. Methods: This was a retrospective study of patients (n = 26,505) with no history of dialysis undergoing primary, isolated OHT between 2000 and 2022 as identified in the United Network for Organ Sharing (UNOS) database. The study cohort was split randomly into training (80%) and validation sets (20%) and under-sampling using K-Nearest Neighbors clustering was used to account for class imbalance. ML models, including a Multilayer Perceptron Classifier, a Support Vector Classifier, and a Logistic Regression Model were developed and compared. Sensitivity, accuracy, precision, and F 1 score were measured, and discriminatory performance was assessed using the area under the receiver-operating-characteristic curve (AUC). Results: The rate of new dialysis was 11.3% following OHT with comparable rates in the training and validation cohorts. In the validation cohort, the support vector classifier had the highest AUC Score (0.774 (95% CI, 0.748 - 0.800), sensitivity (0.74), F 1 Score (0.72), accuracy (0.70), and precision (0.70). All other models yielded poorer performance by every metric. Predictive risk factors that were common across models included congenital heart disease, pre-transplant glomerular filtration rate, and human leukocyte antigen mismatch. Conclusions: This study demonstrates that an ML approach using a support vector model was associated with improved model performance metrics including discriminatory capability compared to other modeling approaches in predicting new-onset dialysis risk after OHT. The use of ML models in OHT may have utility in patient selection, modification of risk factors, and programmatic evaluation.
Abstract 15088: Cholesterol-Induced Suppression of Kir2.1 Contributes to the Development of Atherosclerosis
Authors: Sara T Granados, Natalia Do Couto, Ibra Fancher, Irena Levitan
Journal: Circulation (2022)

Introduction: Our recent studies demonstrated that cholesterol sensitivity of inwardly-rectifying K + channels (Kir2.1) contributes to the impairment of flow-induced vasodilation (FIV) in resistance arteries. Methods: In this study we developed a new CRISPR mouse model, originated from our molecular dynamics research for the Kir 2.1 channel. This model Kir2.1 L222I , has a point mutation (L222I) that renders the channel cholesterol insensitive. We also crossed our new CRISPR model with a dyslipidemic ApoE -/- mice resulting in a ApoE -/- Kir2.1 L222I . We evaluated Kir2.1 channel function with patch clamp for both models. We then placed our mice on a high fat (42% kcal from fat) diet (HFD) from 12 -14 weeks and analyzed atherosclerotic lesions with Oil Red O in En Face aortas and cross sections of carotid arteries for both female and male mice. We also documented weight gain, food consumption and blood biochemistry. Results: A lack of cholesterol sensitivity of Kir2.11 L222I was functionally confirmed in endothelial cells freshly isolated from mesenteric arteries of Kir2.1 L222I and ApoE -/- Kir2.1 L222I mice. We found that ApoE -/- Kir2.1 L222I mice have significant reduction in the area of atherosclerotic lesions in their aortas, as compared to ApoE -/- mice. This phenomenon was observed both in the aortic arch and in the descending aorta. Specifically, the lesion areas in the arch were 37.2± 1.87% (n:8) vs. 20.3 ±2.3% (n:8) in ApoE -/- vs. ApoE -/- Kir2.1 L222I mice respectively. The effect on the lesion area in the descending aorta was even more pronounced: 16.5 ±2.1% (n:8) in ApoE -/- to 5.6± 1.3% (n:8) in ApoE -/- Kir2.1 L222I . The same effect was observed in males and females. In addition, we also analyzed the lesion areas and stenosis in carotid arteries of the same mice and found that ApoE -/- Kir2.1 L222I mice are also partially protected, as compared to ApoE -/- . However, no differences were found in the levels of LDL, HDL and total cholesterol between these mice. Conclusion: Our data suggest that cholesterol-induced suppression of Kir2.1 is an important contributor to the development of atherosclerosis.
Abstract 15081: The Viscoelastic Yield Stress of Blood is Negatively Associated With Pulmonary Blood Flow in the Fontan Circulation
Authors: Silvie Suriany, Honglei Liu, Andrew L Cheng, Jon A Detterich
Journal: Circulation (2022)

Introduction: In the Fontan (FN) circulation pulmonary blood flow (Qp) is passive, resulting in severely decreased shear rate and velocity in pulmonary arteries to the point of stasis. Yield stress (YS) is the shear stress required for blood to transition from stasis to a moving fluid. Therefore, YS may be a determinant of Qp in FN. We evaluated YS in patients with FN and Glenn (GLN) circulations and whether increased YS is associated with decreased Qp. Methods: We enrolled 20 patients with biventricular (2V) congenital heart disease (CHD) and 41 patients with single ventricle CHD (19 FN and 22 GLN) who were undergoing a clinically indicated cardiac catheterization. Two patients were excluded due to pulmonary vascular disease. We obtained blood samples at the time of catheterization and measured blood viscosity across shear rates 1 s -1 to 1000 s -1 using a Rheolog viscometer We calculated YS by curve-fitting of the viscosity measurements to a Casson fluid model. Hypothesis: We hypothesize that higher yield stress will be associated with lower pulmonary blood flow in Fontan circulation. Results: The FN group was the oldest and had the largest BSA (FN&gt;2V&gt;GLN; p&lt;0.0001). Hematocrit was highest in GLN (GLN&gt;FN&gt;2V; p&lt;). Blood viscosity was higher across all shear rates in GLN compared to both FN and 2V (p&lt;0.001 for all shear rates) and higher in FN than 2V from 1 s -1 to 150 s -1 (p&lt;0.05 for all shear rates). YS was highest in GLN (GLN&gt;FN&gt;2V; p&lt; ). YS was negatively associated with Qp in both FN (R2 0.33, p=0.02) and GLN (R2 0.2, p=0.038), but not 2V (see Figure). Hematocrit was negatively associated with Qp in 2V (R2 0.34, p=0.028) and trended toward negative association in FN (R2 0.27, p=0.099), but not in GLN. Stepwise regression of Hct and YS vs Qp in FN demonstrated YS as the primary predictor of Qp. Conclusions: Our data demonstrate that the yield stress of blood derived from the Casson fluid model is a significant determinant of pulmonary blood flow in FN circulation.
Abstract 15110: Objective Quantification of Disease Severity in Patients With Long Covid
Authors: Monica Verduzco-Gutierrez, Juan Cabrera, Marielisa Lopez, Mohanakrishnan Sathyamoorthy, Sachin A Shah, Akil Loli
Journal: Circulation (2022)

Introduction: Patients with Long Covid have been described to present with over 55 subjectively reported symptoms with the most prevalent being fatigue and cardiopulmonary (e.g. chest pain, dyspnea). Objective quantification of the magnitude of disease severity in Long Covid patients using standardized validated tools is needed. Methods: This is a retrospective evaluation of patients referred to Flow Therapy for the management of Long Covid symptoms from Jan 2021 to Jan 2022. Patients were included if having complete data for 6 validated tools: PROMIS Fatigue score (range 0-20), Seattle Angina Questionnaire (SAQ) Summary Score (range 0-100), Duke Activity Status Index (DASI, range 0-58.2), 6-minute walk test (6MWT, range 0-unlimited), Rose Dyspnea Scale (RDS, range 0-4) and CCS angina class (CCS, range 1-4). The unpaired student’s t-test or the Fisher’s exact test were utilized for all analyses. Results: A total of 100 patients were included for analyses (age 54.2±14.5years, 60% female, 41% with CAD). The baseline PROMIS Fatigue, SAQ, DASI, and 6MWT were 15.8±3.6, 58.6±24.5, 12.9±12.7, and 1199.6±428.3 feet respectively. Moderate to severe dyspnea (RDS) or angina (CCS) was reported in 81% and 61% of patients respectively. When limiting to those without CAD (n=59), the PROMIS Fatigue was 15.7±3.4 compared to 16.0±3.6 in those with CAD (p=0.719). When limiting to those under the age of 41 (n=19), the PROMIS Fatigue was 15.9±4.0 compared to 15.8±3.5 in those 41 years or older (p=0.9466). No correlation was evident between age and PROMIS Fatigue score (r=0.107). SAQ and RDS were not different between the CAD and non-CAD patients (all p-values&gt;0.111). There was no difference across all endpoints when comparing those under 41 versus 41 years or older (all p-values&gt;0.087). Conclusion: Our data indicate a moderately high degree of disease severity using 6 validated markers assessing Long Covid symptoms. The validity of scores in patients with Long COVID applies to both patients with concurrent epicardial disease and patients without known epicardial disease. The severity of fatigue in Long Covid patients under 41 is similar to those 41 years or older. Our data provide a paradigm to more objectively diagnose Long Covid.
Abstract 15168: Plasma Metabolomic Profiling Identifies Markers of Cardiorespiratory Fitness Responsive to Endurance Exercise Training
Authors: Prashant Rao, Michael Mi, Jacob Barber, Shuliang Deng, Laurie Farrell, Claude Bouchard, Clary Clish, Mark A Sarzynski, Robert E Gerszten, Jeremy Robbins
Journal: Circulation (2022)

Background: High-throughput metabolite profiling allows for the assessment of thousands of metabolites that may participate in exercise-related pathways. Here, we characterize plasma metabolite changes in healthy individuals undergoing endurance exercise training (ET) to identify biochemical features of VO 2 max and/or those responsive to ET. Methods: We measured 444 known metabolites and 3221 non-targeted metabolite peaks using liquid chromatography tandem mass spectrometry and VO 2 max using CPET before and after 20 weeks of supervised, endurance ET in 654 sedentary participants (mean age=34y; 39% self-identified Black) from the HERITAGE Study. Multivariate linear regression assessed the relation between metabolites and baseline VO 2 max (ml·kg –1 ·min –1 ), adjusting for age, sex, and race. Changes after ET were determined using paired t tests. We used a false discovery rate (q) &lt; 0.05 to determine statistical significance. Results: 494 metabolites were associated with VO 2 max, the majority (375/494) of which were non-targeted (unknown) metabolites with greater effect sizes than targeted peaks [β range: -29.66 - 17.80 and -22.76 - 12.87 for unknown and known metabolites]. We recapitulated known metabolite associations with VO 2 max including DMGV, branched chain amino acids, and uric acid ( Figure 1 ). 110 of 560 metabolites that changed after ET were associated with VO 2 max, including non-targeted peaks that concordantly changed after ET (e.g. metabolite peaks positively associated with VO 2 max that increased with ET; m/z 385.3056 and 695.5086; β for VO 2 max = 9.82 and -19.33, q= 5.56e-7 and 2.61e-17, and log fold-change = 0.03 and -0.01, q=9.58e-13 and 1.93e-4, respectively). Conclusions: We identified novel metabolite peaks associated with VO 2 max that concordantly changed after ET. Non-targeted metabolomic profiling reveals new markers related to VO 2 max and exercise response, motivating ongoing work to unambiguously identify these compounds.
Abstract 14996: Single Cell Rnaseq Analysis Reveals a Two-Step Mechanism for the Reprogramming of Ventricular Myocytes to Pacemaker Cells by Tbx18
Authors: Jinqi Fan, Hee Cheol Cho
Journal: Circulation (2022)

Background: We have demonstrated that an embryonic transcription factor, TBX18, suffices to reprogram ventricular myocytes (VMs) to induced pacemaker cells (iPMs). Here, we sought to gain a mechanistic understanding of the reprogramming process using single cell (sc) RNAseq analysis. Methods: Cells from the ventricles of the neonatal rat heart were plated as monolayers, which consisted of both cardiomyocytes (CMs) and nonmyocytes, and were transduced with Adeno-GFP and Adeno-TBX18 in vitro. scRNAseq was performed at days (d) 3, 6, and 14. Result: TBX18- CMs exhibited repression of chamber CM genes at d3, including those involved in cardiac muscle contraction and action potential. Markers of CM dedifferentiation ( Acta2 and Dab2 ) were upregulated, while markers of chamber CM differentiation ( Mef2a and Rbm20 ) were downregulated. Nodal pacemaker cell gene expression followed the CM dedifferentiation in TBX18-CMs, with the proportion of Hcn4 + CMs increasing gradually from 20.9% (d3) to 34.0% (d14), accompanied by increased expression of Tbx3 and Tbx18 . The proportion of iPMs ( Hcn4 + , Gja1 low , Nkx2-5 low , Tnni3 high , and Actn2 high ) in TBX18-CMs also increased from 3.6% at d3 to 6.4% at d14. Both TBX18-CMs and GFP-CMs exhibited a subpopulation of Acta2 high dedifferentiated CMs (deCMs), which were represented higher in TBX18-CMs compared to control. Among TBX18-CM subpopulations, the proportion of iPMs was the highest in deCMs (6.4% at d3 and 7.3% at d14). TBX18-deCMs were distinct from other TBX18-CM subpopulations in that extracellular matrix organization and Tgfβ signaling were enriched as well as higher expression of SP1 transcription factor which directly activates Hcn4 channel expression. Conclusion: Dedifferentiation and loss of CM function precedes nodal pacemaker cell gain of function during TBX18-induced somatic reprogramming of VMs to iPMs. Tgfβ signaling appears to figure prominently during this process.
Abstract 15185: BRD4-Mediated Genome Folding Controls Fibroblast Cell State Transition
Authors: Rachel Yang, Zachary Gardner, Bailey Koch-Bojalad, Wonho Kim, Son C Nguyen, Eric F Joyce, Arun Padmanabhan, Rajan Jain
Journal: Circulation (2022)

Introduction: Cardiac fibrosis is mediated by the activation of fibroblasts to myofibroblasts, a cell state transition which involves the coordination of expression of hundreds of genes. Previous studies have demonstrated that inhibition of bromodomain and extra-terminal domain (BET) proteins attenuates fibrosis. We recently discovered a novel role of bromodomain-containing protein 4 (BRD4), a BET family member, in maintaining genome folding by stabilizing the cohesin complex (necessary for genome-genome interactions). We hypothesize that BRD4-mediated genome folding is critical for maintaining the enhancer-promoter interactions at genes required for fibroblast activation. Methods: A cardiac fibroblast cell line was generated in which a degron epitope tag was appended biallelically to Brd4 to enable acute BRD4 degradation. Fibroblasts were activated via addition of TGFβ. Meox1 , a critical transcription factor mediating a broad fibrotic gene program, was used as a model locus to investigate chromatin looping. The proximity between the Meox1 enhancer and promoter, Meox1 expression, and protein occupancy at the locus were determined using DNA fluorescence in situ hybridization, RT-qPCR, and chromatin immunoprecipitation (ChIP)-qPCR, respectively. Results: The proximity between the Meox1 enhancer and promoter and Meox1 expression increased upon TGFβ-induced activation. BRD4 occupancy was enriched at the enhancer of Meox1 upon activation, and BRD4 depletion reduced Meox1 expression and the co-localization of the Meox1 enhancer and promoter. BRD4 physically interacts with the cohesin agonist NIPBL, and we found that co-depletion of BRD4 and a cohesin antagonist normalizes the Meox1 enhancer and promoter proximity and Meox1 expression levels. Ongoing studies include genome-wide occupancy studies and expanding our findings to in vivo models of cardiac fibrosis. Conclusions: Our studies provide a mechanistic understanding of the functional relevance of genome organization during fibroblast activation. These studies will also expand our knowledge on how genome folding regulates cell plasticity and inform therapeutic approaches for targeting pathologic fibrotic remodeling.
Abstract 15115: Causes and Predictors of 90-Day Readmission Among Patients Admitted With Acute Myocarditis
Authors: Ufuk Vardar, Ramtej Atluri, Mukunthan Murthi, Dennis Kumi, Anoj Shahi
Journal: Circulation (2022)

Introduction: Myocarditis contributes to the global burden of cardiovascular disease primarily through sudden death and dilated cardiomyopathy. We aimed to study patient characteristics, national readmission rates and predictors for patients admitted for acute myocarditis utilizing a nationally representative cohort of patients from the National Readmission Database. Methods: We utilized the National Readmission Database 2018 to identify the hospitalized adults with a primary diagnosis of acute myocarditis. We included subjects who were readmitted within 90 days after index admission. We excluded subjects with elective and traumatic admissions. We utilized a multivariate cox regression model to identify independent predictors of readmission. Results: During the study period, 3,524 hospitalized patients who had a primary diagnosis of acute myocarditis were discharged alive. Within 90 days of discharge, 356 (10.1%) subjects were readmitted. The top three causes of readmission were heart failure (37.1%), sepsis (16.1%) and ventricular tachycardia (10.6%). The in-hospital mortality rate (5.5 vs. 2.6%, p&lt;0.001) was significantly higher during readmission. There was a trend in higher length of stay in readmission (5.6 vs. 4.3 days, p=0.055), however this difference was not statistically significant. Figure 1 shows the Forest plot of multivariate analysis of independent factors associated with readmissions. Conclusion: Our study identified significant factors such as heart failure, atrial fibrillation, hypertension related to higher readmission odds for myocarditis patients. This data may contribute to the healthcare system to help modify strategies to minimize readmission.
Abstract 15102: Short- versus Long-Term Recurrence of Ventricular Tachycardia in Non-Ischemic Cardiomyopathy: Is It Due to Incomplete Ablation During the Index Procedure or Progression of the Disease? Results From a Single-Center Study
Authors: Sanghamitra Mohanty, Sai Shishir Shetty, Karim Baho, Domenico G Della Rocca, ANGEL QUINTERO MAYEDO, Bryan MacDonald, carola gianni, Trevor Morris, Issa Asfour, Danielle Kessler, Mohamed Bassiouny, G Gallinghouse, John Burkhardt, Rodney Horton, Amin Al-Ahmad, Luigi Di Biase, Andrea Natale
Journal: Circulation (2022)

Background: Non-ischemic cardiomyopathies (NICM) occur in the absence of contributory coronary artery disease or significant valvular heart disease. This study examined if VT recurrence post-scar-homogenization in NICM patients was due to progression of the disease after successful ablation or incomplete ablation during the index procedure. Methods: Consecutive NICM patients receiving redo procedure after their 1st VT ablation were included. All patients underwent bipolar substrate mapping with standard scar settings of normal tissue &gt;1.5 mV and severe scar &lt;0.5 mV. Endocardial scar homogenization was followed by heparin reversal with protamine and subsequent epicardial ablation. Disease progression was defined as extension of index scar area or appearance of new scar and decline in the baseline left ventricular ejection fraction (LVEF). Incomplete ablation was described as ablation within the index scar area that was ablated in the earlier procedure. Recurrence within 12 months was considered as early recurrence . Results: A total of 310 NICM patients (age: 60±13.5 years; male: 231 (74%); LVEF: 37±11%) undergoing their first VT ablation procedure were followed up for 7 years, of which 38 (12.2%) experienced recurrence and underwent re-ablation. Of the 38, 13 received repeat ablation at 5.07±2.56 months ( early recurrence ) and the remaining 25 patients had the redo at 40±21.78 months ( late recurrence ). In these 38 patients, mean LVEF was significantly lower at redo (pre-index: 35.3±10.6; pre-redo: 30.2± 7.07%, p=0.015). In the early-recurrence group , 10 (77%) had ablation sites located within the index scar (incomplete ablation) and 3 (33%) had extension of the index scar area (disease progression) detected. Index scars were mostly mid-myocardial (11, 84.6%). In the late-recurrence cohort , extension of the index scar area was detected in 12 (48%) and new scar were mapped in 19 (76%); none of these patients had incomplete ablation noted. Conclusion: In NICM patients, VT recurrence within 1-year of index procedure was mostly associated with incomplete ablation of mid-myocardial scars, whereas disease progression evidenced by detection of new scar, extension of preexisting scar and decline in LVEF was prevalent in patients with very late recurrence.